Due to ease accessibility, exploring plasma for candidate cancer biomarkers is of great interest to molecular biologist and physicians. In breast cancer, the development of tamoxifen resistance (TR) is among the major causes of recurrence and mortality. Therefore, the identification of novel biomarkers that are linked to TR is of great interest and the subject of intensive research. Here, we exploited the power of two-dimensional gel electrophoresis coupled with protein identification using tandem mass spectrometry to identify plasma proteome signatures associated with TR. Comparative proteomics analysis resulted in the identification of 15 statistically significant spots, which were up-/downregulated after tamoxifen therapy. MASCOT search of the mass spectrometry generated spectral data resulted in the identification of 9 proteins. Several differentially expressed proteins such as clusterin, serum amyloid A, serpin B4, and transthyretin are already known to be involved in cancer incidence and progression. The possible involvement of these candidate proteins in conferring TR and their potential usefulness as plasma biomarkers for predicting response to tamoxifen treatment has been discussed.